Combination of desoxypeganine and mecamylanine for the treatment of alcohol abuse

ABSTRACT

An active substance combination comprising deoxypeganine or of one of its pharmaceutically acceptable derivatives and mecamylamine or one of its pharmaceutically acceptable derivatives. The active substance combination serves to produce a medicament for the treatment of alcohol abuse and/or alcohol dependence.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application of InternationalApplication No. PCT/EP2004/004033, filed on Apr. 16, 2004, which claimspriority of German application number 103 18 714.6, filed on Apr. 25,2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pharmaceutical preparations containing3-deoxypeganine and/or mecamylamine. The invention further relates tothe use of this active substance combination for treating theconsumption of alcohol, which is detrimental to health, as well asalcohol dependence.

2. Description of the Prior Art

Problem

Of the numerous psychotropic substances with abuse potential, ethanol(in general usage referred to as “alcohol”) is the oldest, the mostwidely used and the by far most significant in terms of its effects onhealth and its social and economic consequences. It is assumed that inGermany approximately 1.6 million people are clinically dependent onalcohol, and that 2.7 million consume alcohol on a medically injuriouslevel. About 5 million people must be regarded as being at risk. Everyyear about 40,000 people—these are by no means only persons clinicallydependent on alcohol but also those practicing high-risk consumption ofalcohol over extended periods—die each year from the direct consequencesof consumption of alcohol. Characteristically, the number of thesedeaths, as well as that of alcohol cessation therapies, has remainedsubstantially constant in the western industrialized states, althoughthe overall consumption of alcohol has been continuously decreasing foryears. This permits the conclusion that the decrease in the overallconsumption of alcohol is due above all to wide sections of consumerswho have already in the past been relatively health-consciousrestricting or foregoing consumption of alcohol, whereas the spreadingof high-risk or detrimental consumption of alcohol remains unaltered.

There is thus the task of pharmacologically assisting the reduction ofhigh-risk or detrimental consumption of alcohol—also and particularly ofthat consumption behaviour which does not yet involve clinicaldependence.

State of Science and State of the Art

In European states and/or in the United States of America there arecurrently five preparations which have approval for use in the drugtherapy of alcohol abuse. Of these,bis(diethylthiocarbamoyl)disulfide(disulfiram, ANTABUS®), which has beenin use longer than any of the other preparations, has only an aversiveeffect which does not influence the actual craving for alcohol. Whereastiapride, a dopamine antagonist operating on the receptor subtypes D2and D3, has gained little practical significance, the opiatereceptor-antagonist naltrexone (REVIA®, DuPont; TREXAN®), and acamprosat(N-acetyl homotaurinate; CAMPRAL®, Merck AG; AOTAL®), which in a complexmanner has anti-excitatory action and also influences noradrenergic anddopaminergic pathways, are utilized to a far greater extent, followingacute withdrawal, to prevent relapses to abuse of alcohol. Recently, insome European countries the antiexcitatory gamma-hydroxybutyrate (e.gALCOVER®, Gerot Pharmazeutika) has become available. Naltrexone andgamma-hydroxybutyrate, however, cause considerable gastrointestinal andpsychomotoric side effects which impair therapy compliance. In addition,naltrexone is characterized by its low oral bioavailability (approx. 5%of the amount taken in becomes effective) and it is moreoverhepatotoxic, whereas gamma-hydroxybutyrate has addiction potentialitself.

The long-term success of all the pharmaceutics indicated herein must beregarded as altogether very limited since in the majority of patientsthey cause an only marginal relapse delay after withdrawal or aclinically insignificant reduction of the amount of alcohol consumed.These medicaments have not had a lasting influence on the fact that onaverage only 30% of all patients are still abstinent a year afterwithdrawal treatment.

The therapy of the early stages of a development towards clinicalalcohol dependence often spanning several decades (ICD-10 Code F10.2 ofthe World Health Organization, WHO) and especially the medicinallydetrimental consumption of alcohol not yet involving clinical dependencebut nevertheless involving high physical and psychiatric potential fordamage (ICD-10 Code F 10.1) would, in addition, require medicamentshaving very few side effects since the so-called “social drinkers”, dueto experiencing as yet only little suffering, have hardly anyunderstanding of the problematical nature of their drinking behaviourand therefore show little willingness to suffer such side effects.

Alcohol and all other addiction-producing substances share the abilityof activating dopaminergic neurons in the mesolimbic system whichrepresents a central component of the pleasure- andsatisfaction-imparting “reward system” in the brain. A dopaminergictherapy may be carried out either via the direct route (by dopaminereceptor agonists such as lisuride or bromocriptine) or indirectly byincreasing the dopamine concentration locally available in the synapticgap (e.g. by inhibiting the degradation of the neurotransmitters bymonoamine oxidases).

However, the pharmacology of alcohol is complicated, which also findsexpression in the above-described diversity of therapeutic approaches.According to current opinion the, on the one hand, sedating and, on theother hand, euphoretic effects and the cognitive- andmotor-coordination-impairing effects of alcohol are due to the fact thatethanol shows interactions with the protein subunits of many neuronalreceptors and thereby modulates their function. Receptors whichrepresent ion channels are particularly affected by this; in fact theyare affected already at concentrations which are by far too low tolastingly impair neuronal membrane structures.

A special position in the therapy of alcoholism which has as yetreceived little attention is taken up by modulators of cholinergicneurotransmission; these particularly include cholinesterase inhibitors.On the one hand, cholinergically active medicaments are able to enhancethe cognition impaired by alcohol-induced damage of the cholinergicpathways and thus increase insight into the problem; on the other hand,cholinergic therapies can also bring about a direct, not cognitivelyinduced reduction in the craving for alcohol. According to currentknowledge, this is brought about by the neuronal nicotinic acetylcholinereceptors (NACHRs) which are located not only on cholinergic but also ondopaminergic neurons in the mesolimbic system. These receptors arestimulated by an increase in the acetylcholine concentration, and inresponse thereto release higher amounts of dopamine. They therebystimulate alcohol-induced dopamine release but without having theeffects which alcohol has on other receptors and without causingextremely high dopamine concentrations, so that no significant addictionbehaviour is induced. This therapeutic approach could in a wider sensebe referred to as partial substitution therapy.

Deoxypeganine (1,2,3,9-tetrahydropyrrollo[2,1-b]chinazoline) is acholinesterase inhibitor which in pharmacologically relevantconcentrations does not bind to NACHRs and which additionally inhibitsmonoamine oxidase A (but not monoamine oxidase B). This substance isalso excellently suitable for the therapy of alcohol abuse, as describedby DE 199 06 974 and by the publications WO 00/48600 and EP 1 154 776.

An approach entirely opposite to that of partial substitution therapy isthe therapy of substance consumption by blocking the receptor systemswhich are activated by the respective agonistically active drug ofabuse; however, in the case of an existing substance dependence, thistherapy can produce withdrawal symptoms which means that there is a highprobability of relapse into substance consumption. This applies, forexample, to the treatment of nicotine abuse by blocking NACHRs by meansof mecamylamine (N-(2,2,3-tetramethyl-bicyclo[2.1.1.]heptane-2-amine).

This racemic mixture of the optical isomers exo-S(+) andexo-R(−)-mecamylamine is an almost 100% orally bioavailable,CNS-penetrant, non-subtype-specific and non-competitive antagonist atneuronal NACHRs which in 1956 was introduced in therapy as anantihypertonic under the trade mark INVERSENE® and INVERSINE®. The twostereoisomers show a differentiated, but essentially comparablebehaviour at the individual NACHR subtypes, with the exo-S(+) isomerpossibly having a certain selectivity for neuronal NACHRs and therebyreduced peripheral side effects, in particular, on the muscular system.Since mecamylamine in the doses effective for the treatment of essentialhypertension of 25 mg/day causes an extensive blockade of theparasympathetic nervous system and thereby leads to an abundance ofcorresponding side effects, it has been applied only in exceptionalcases since 1977. In 2000, mecamylamine was reintroduced in the USA forexperimental therapy of certain neuropsychiatric diseases.

U.S. Pat. No. 6,083,962 claims combinations of respective specificantagonists and the substances acting as agonists on respectivecorresponding receptors and having abuse potential, especiallycombinations of mecamylamine and nicotine for the therapy of nicotineabuse. This is based on the idea that it should be possible to activatepart of the NACHRs by administering nicotine in a pharmacologicallysuitable, non-addiction-producing form (by an administration form,particularly a transdermal administration form, causing a uniform andcontrolled release) and thereby satisfy the primary craving for nicotinebut prevent the continued consumption thereof by blocking the remainingNACHRs by simultaneously administered mecamylamine. In fact, asynergistic effect of such a fixed active substance combination could beshown in a pilot study, and the effect could even be enhanced byadministering mecamylamine singly, prior to smoking cessation (Drug DevRes 1996; 38:243-56; Exp Clin Phyhopharmacol 1998; 6(3): 33143).According to the results reported in 1998 of three Phase III studies,however, a transdermally administered fixed active substance combinationhad proved not to be superior to the nicotine patch. However, none ofthe aformentioned documents addresses the subject of alcohol abuse.

Blomqvist et al, in Eur J Pharmacol 1993; 249(2): 207-13 and Eur JPharmacol 1997; 334 (2-3): 149-56, teach that mecamylamine completelyblocks alcohol-induced increase in extracellular dopamine concentrationin the nucleus accumbens of the rat, but without impairing thephysiologically significant baseline level of the dopamine release. Thisis therefore a blockade of the dopaminergic component of the effect ofalcohol which in the context of the above described basis is regarded bythe authors as an indirect effect mediated by NACHRs. Furthermore,making reference to the above papers as a theoretic basis, Alcohol ClinExp Res 2002; 26: 326-31 describes a trial on healthy probands who didnot exercise alcohol or nicotine abuse. In this study mecamylamine,administered two hours prior to consumption of alcoholic beverages,reduced the centrally stimulating psychotropic effect and presumablyalso the pharmacokinetics of alcohol. None of these three papersmentions the combination and/or simultaneous administration ofmecamylamine with other pharmacologically active substances, inparticular, with cholinesterase inhibitors or nicotinic agonists.

The published applications WO 00/35279 and WO 00/35280 claim the twoisomers of mecamylamine for the therapy of a plurality of conditionsrequiring medical treatment, inter alia of alcohol abuse. However, withrespect to this option these documents neither indicate biological datanor do they mention any combinations with other pharmacologically activesubstances for this therapeutic purpose.

SUMMARY OF THE INVENTION

In light of the above-described state of science, particularly in lightof the fact that the pharmacology of alcohol abuse is far more complexthan the habit-forming effect of nicotine, a person skilled in the artcould by no means assume that deoxypeganine, a substance which actsindirectly on NACHRs due to an increase in the central acetylcholineconcentration, would show synergistic action with mecamylamine (a directinhibitor of NACHRs) with regard to the reduction of alcohol consumptionand alcohol preference as compared to non-alcoholic beverages.Surprisingly, this is precisely what is the case.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph depicting ethanol preference in female AA ratsduring the first four and subsequent eight hours after treatment.

FIG. 2 is a bar graph depicting consumption of ethanol in female AA ratsfour hours and eight hours after treatment.

DETAILED DESCRIPTION OF THE INVENTION

The subject matter of the invention is thus the combined use ofdeoxypeganine and mecamylamine to reduce alcohol consumption. Treatmentmay be performed either by simultaneously administering the two activesubstances, or by administering mecamylamine singly, immediatelyfollowed by a combination of the active substances according to thepresent invention.

EXAMPLE 1 Reduction of Alcohol Consumption and Alcohol Preference inAlcohol-Preferring Rats

The “AA” strain of rats, bred in Finland, has a genetically determinedpreference for alcohol, which means that even without pre-treatment withalcohol the animals, when given free choice, prefer alcohol-containingliquids, to alcohol-free liquids to satisfy their fluid requirement.This strain has therefore been used in numerous studies on thepharmacology of alcohol and is extremely well characterized.

Female AA rats (tested for alcohol preference and made available by thePublic Health Institute in Helsinki) were housed individually and hadfree access to standard feed (Altromin 1324 granulate), the ambienttemperature was 24±1° C. and the light-dark change was 12/12 hours (thedark period lasting from 6 p.m. to 6 a.m. Each cage contained twoidentical drinking bottles, of which one contained pure water and theother contained aqueous ethanol (10% v/v). During the 12-hour darkperiod the animals had access to the drinking bottles and during thisperiod had free choice between the two solutions. To prevent the animalsfrom becoming accustomed to a particular position in the cage, thepositions of the bottles were changed daily. Prior to start of thetests, the animals were granted an adaptation phase until a largelyconstant alcohol and water consumption was ensured.

Deoxypeganine hydrochloride (called “DOP” in the following) was obtainedfrom the Institute for the Pharmacology of Plants (Taschkent,Usbekistan) and supplied by the firm of LTS Lohmann Therapie-Systeme(Andemach, Germany) after checking for identity and purity. Mecamylaminewas obtained as a commercial preparation from Sigma-Aldrich GmbH(Munich).

Treatment of the test animals always took place immediately prior to thestart of the dark period. Mecamylamine was dissolved in 0.9% aqueoussaline and a volume of 5 ml/kg body weight was administered byintraperitoneal injection. DOP was applied as an aqueous solution with avolume of 10 ml/kg by a probang.

In the case of combination treatments, this administration took placewithin a period of less than 10 minutes. Two treatment-free days werealways interposed prior to and following the treatment days.

The parameters recorded were consumption of alcohol, consumption ofwater and consumption of feed (each in grams), as well as alcoholpreference, calculated using the formula:${{Alcohol}\quad{preference}\quad{in}\quad\%} = \frac{\begin{pmatrix}{{consumption}\quad{of}\quad{alcohol}\text{-}{containing}} \\{{drinking}\quad{solution} \times 100}\end{pmatrix}}{\left( {{total}\quad{consumption}\quad{of}\quad{fluid}} \right)}$

The target parameters were in each case traced during the 12 hours ofthe dark period following treatment, intermediate results were recordedafter the first 4 hours and final results after 12 hours. Statisticalevaluation of the test data was performed using the t-test for dependentvalues. The results in respect of consumption of alcohol and alcoholpreference are summarized in FIGS. 1 and 2 as well as in Tables 1 and 2.TABLE 1 Synergism between deoxypeganine p.o. (DOP) and mecamylamine i.p.(Mec) in reducing alcohol preference in female AA rats ALCOHOLPREFERENCE (%) TREATMENT After 4 hours After 8 hours Total Trial DOP 20mg/kg 57.4 ± 7.1 82.0 ± 4.0 70.5 ± 4.5 1 DOP 20 mg/kg + Mec 43.3 ± 6.5*)66.9 ± 5.7*) 69.4 ± 5.8*) 1.0 mg/kg Trial DOP 20 mg/kg 55.6 ± 7.6 88.0 ±2.1 72.7 ± 4.3 2 Mec 1 mg/kg 85.3 ± 4.2 87.8 ± 3.1 86.3 ± 2.6 DOP 20mg/kg + Mec 47.2 ± 8.2 76.5 ± 6.3 66.6 ± 6.8 1.5 mg/kg DOP 20 mg/kg +Mec 47.7 ± 10.1 71.7 ± 6.5*) 61.1 ± 6.5*) 1.0 mg/kg DOP 20 mg/kg + Mec54.8 ± 7.7 79.6 ± 5.8 71.6 ± 5.3 0.75 mg/kg DOP 20 mg/kg + Mec 59.6 ±7.3 80.9 ± 4.2 72.8 ± 4.1 0.5 mg/kg*)Difference significant (p < 0.05) compared to DOP 20 mg/kg in therespective trial

With peroral administration of 20 mg/kg p.o., DOP lowered theconsumption of alcohol and alcohol preference, preferably within thefirst 4 hours after administration. Mecamylamine (1 mg/kg i.p.) had noeffect when administered singly, but potentiated the effect of DOP onboth parameters. Low dosages of mecamylamine (0.5, respectively 0.75mg/kg i.p.) were without effect with regard to alcohol, while thepotentiating effect could not be increased further by increasing themecamylamine dosage to 1.5 mg/kg i.p. (Tables 1 and 2). TABLE 2Synergism between deoxypeganine p.o. (DOP) and mecamylamine i.p. (Mec)in reducing the consumption of 10% aqueous ethanol solution in female AArats. Alcohol solution consumed (gram) TREATMENT After 4 hours After 8hours Total Trial DOP 20 mg/kg 5.2 ± 0.6 10.2 ± 0.6 15.4 ± 1.1 1 DOP 20mg/kg + 2.3 ± 0.3**)  7.9 ± 0.07**) 10.2 ± 0.9**) Mec 1.0 mg/kg TrialDOP 20 mg/kg 5.8 ± 0.6 10.7 ± 0.5 16.6 ± 0.6 2 Mec 1 mg/kg 5.4 ± 0.510.1 ± 0.4 15.5 ± 0.5 DOP 20 mg/kg + 2.6 ± 0.4**)  8.5 ± 0.7**) 11.1 ±1.0*) Mec 1.5 mg/kg DOP 20 mg/kg + 2.8 ± 0.5**)  7.6 ± 0.8**) 10.4 ±1.0**) Mec 1.0 mg/kg DOP 20 mg/kg + 3.4 ± 0.6 10.6 ± 1.1 14.1 ± 1.2 Mec0.75 mg/kg DOP 20 mg/kg + 3.7 ± 0.5  9.9 ± 0.6 13.6 ± 0.6 Mec 0.5 mg/kg**)Difference highly significant (p < 0.01 or p < 0.001) compared to DOP20 mg/kg in the respective trialForms of Administration and Treatment According to the Invention

Administration according to the invention may either be in the form of asingle medicament with a fixed combination of the two active substances,or be accomplished by administering the active substances in separateforms of administration.

According to the invention the administration of deoxypeganine-HCl maybe in the form of tablets or capsules. The daily dose in this case maybe 50 to 750 mg, with a daily dose of 100 to 400 mg, which may bedivided into an arbitrary number of single doses, being preferred.Furthermore, it is possible to utilise utilize deoxypeganine-containingtransdermal therapeutic systems as well as oral and parenteraladministration forms with delayed release, as claimed in DE-199 06 974and the publications WO 00/48600 and EP-1 154 776 derived therefrom, thedaily dose being 50-250 mg, preferably administered in a single dose.

According to the invention, the administration of mecamylamine may beperformed via the oral route, for instance in the form of thepreparation Inversin™ (Targacept, Inc., USA; tablets containing 2.5 mgof racemic mecamylamine hydrochloride); the daily dose may be 2.5-20 mg,with a daily dose of 2.5 to 7.5 mg being preferred. Also usable aretransdermal systems or oral administration forms with delayed releaseformulated according to conventional galenic methods. The daily dose inthis case is 0.5-10 mg, preferably administered in a single dose.

According to the invention, the administration of deoxypeganine andmecamylamine may also be performed in the form of medicaments containingfixed combinations of the two active substances which, depending on themode of administration, are adapted such that the daily dose ofdeoxypeganine can be 50 to 750 mg and that of mecamylamine 0.5-20 mg.

To those skilled in the art it goes without saying that this enumerationis only by way of example and does not in any way exclude the use ofknown derivatives of the above-indicated compounds. Thus, in place ofthe hydrochloride salt of deoxypeganine it is also possible to use itsother physiologically tolerable salts or addition compounds, and forcertain administration forms the free base, especially for transdermalformulations. Likewise, instead of deoxypeganine one may also utilizethe derivatives thereof described in the literature insofar as they arecholinesterase inhibitors. These include 7-bromodeoxypeganine, describedin Synthetic Communs. 25(4), 569-572 (1995),7-halo-6-hydroxy-5-methoxydeoxypeganine,7-bromo-6-hydroxy-5-methoxydeoxypeganine,7-chloro-6-hydroxy-5-methoxydeoxypeganine,7-fluoro-6-hydroxy-5-methoxydeoxypeganine, and7-iodo-6-hydroxy-5-methoxydeoxypeganine, which are described in DrugDes. Disc. 14, 1-14 (1996), as well as the derivatives of deoxypeganinedescribed in Ind. J Chem. 24B, 789-790 (1985); it is to be borne inmind, however, that above all in the older literature deoxypeganine isfrequently referred to under the name of deoxyvasicine.

In the case of mecamylamine, not only the racemate, which is traded e.g.under the name of INVERSINE®, but also each one of the two isomersdescribed in WO 00/35279 and WO 00/35280, also in the form of therespective pharmaceutically acceptable salts and addition compounds, canbe used to produce the administration forms according to the invention.The term “salts” is, predominantly but not exclusively, understood tomean the salts of the inventive compounds with halogen acids and withsimple organic acids such as tartaric acid (tartrates), succinic acid(succinates), maleic acid (maleates) etc.

Furthermore, according to the invention the above-described treatmentwith combinations of deoxypeganine and mecamylamine may be preceded by atreatment exclusively with racemic mecamylamine or its individualisomers which is carried through with daily doses of between 0.5 and 20mg and may last between one day and five days.

The medicament forms utilized according to the present invention toadminister a combination of 3-deoxypeganine or of one of itspharmaceutically acceptable derivatives with mecamylamine or with one ofits pharmaceutically acceptable derivatives, may contain one or more ofthe following additives:

-   -   anti-oxidants, synergists, stabilisers;    -   preservatives;    -   taste corrigents;    -   solvents, solubilizers;    -   surface-active agents (emulsifiers, solubilizers, wetting        agents, defoamers);    -   viscosity and consistency-influencing agents, gelling agents;    -   absorption-accelerating agents;    -   adsorbents, humectants, lubricants;    -   disintegration- and solution-influencing agents, fillers        (extenders), peptizers; and    -   release-retarding agents.

This enumeration is not complete; the suitable physiologicallyacceptable substances are known to those skilled in the art.

The administration of 3-deoxypeganine or one of its pharmaceuticallyacceptable derivatives with mecamylamine or with one of itspharmaceutically acceptable derivatives may take place via the oral orparenteral route. For oral administration it is possible to producemedicaments in known administration forms such as tablets, coatedtablets or lozenges. Apart from these, liquid or semi-liquidadministration forms are also suitable; the active substance in thiscase is present as a solution or suspension. Water, aqueous media orpharmacologically acceptable oils (vegetable or mineral oils) may beused as solvents or suspending agents.

Preferably, the medicaments containing a combination of 3-deoxypeganineor one of its pharmaceutically acceptable derivatives with mecamylamineor one of its pharmaceutically acceptable derivatives are formulated asdepot medicaments, which are capable of delivering these activesubstances to the organism in a controlled manner over an extendedperiod of time.

Moreover, according to the invention the administration of a combinationof 3-deoxypeganine or one of its pharmaceutically acceptable derivativeswith mecamylamine or one of its pharmaceutically acceptable derivativescan also take place via the parenteral route. To this end, transdermalor transmucosal administration forms can be utilized for the inventiveadministration of a combination of 3-deoxypeganine or one of itspharmaceutically acceptable derivatives with mecamylamine or one of itspharmaceutically acceptable derivatives to particular advantage,especially adhesive transdermal therapeutic systems (active substancepatches). With these, it is possible to deliver the active substance tothe patient via the skin, in a controlled fashion and over an extendedperiod of time.

A further advantage is that improper use is more difficult withparenteral application forms than with oral administration forms.Because of the preset active substance-release surface and thepredetermined release rate, one can largely exclude overdosage on thepart of the patient. In addition, transdermal administration forms arevery advantageous because of further properties, e.g. avoiding thefirst-pass effect or enabling a better, more uniform control of theblood level.

Such transdermal systems containing a combination of 3-deoxypeganine orone of its pharmaceutically acceptable derivatives with mecamylamine orone of its pharmaceutically acceptable derivatives usually comprise anactive substance-containing, pressure sensitive adhesive polymer matrixwhich is covered on the side averted from the skin by an activesubstance-impermeable backing layer and whose adhesive, activesubstance-releasing surface is covered with a detachable protectivelayer prior to application.

The production of such systems and the basic materials and auxiliarymaterials which may be used in the production are in principle known tothose skilled in the art; the structure of such transdermal therapeuticsystems, for example, is described in the German patents DE 33 15 272and DE 38 43 239, or in the U.S. Pat. No. 4,769,028, 5,089,267,3,742,951, 3,797,494, 3,996,934 and 4,031,894.

As an alternative embodiment of transdermal therapeutic systems in patchform intended for the administration of the inventive active substancecombination, so-called reservoir systems may be taken into considerationwherein the active substances are present in a bag which at least on theskin-side consists of a membrane that is permeable to the activesubstances.

The inventive combination of 3-deoxypeganine or of one of itspharmaceutically acceptable derivatives with mecamylamine or with one ofits pharmaceutically acceptable derivatives can be utilized in thetherapy of consumption of alcohol which is injurious to health as wellas of alcohol dependence in order to reduce the consumption of alcohol.

The inventive combination of 3-deoxypeganine or one of itspharmaceutically acceptable derivatives with mecamylamine or one of itspharmaceutically acceptable derivatives may be utilized for theproduction of medicaments intended for the therapy of alcohol abuseand/or alcohol dependence, especially to reduce the consumption ofalcohol.

What has been described above are preferred aspects of the presentinvention. It is of course not possible to describe every conceivablecombination of components or methodologies for purposes of describingthe present invention, but one of ordinary skill in the art willrecognize that many further combinations and permutations of the presentinvention are possible. Accordingly, the present invention is intendedto embrace all such alterations, combinations, modifications, andvariations that fall within the spirit and scope of the appended claims.

1. An active substance combination comprising deoxypeganine or one ofits pharmaceutically acceptable derivatives and mecamylamine or one ofits pharmaceutically acceptable derivatives for the production of amedicament for treating alcohol abuse and/or alcohol dependence.
 2. Theactive substance combination according to claim 1, wherein thepharmaceutically acceptable derivative of deoxypeganine is selected fromthe group consisting of deoxypeganine hydrochloride,7-bromodeoxypeganine, 7-bromo-6-hydroxy-5-methoxydeoxypeganine,7-chloro-6-hydroxy-5-methoxydeoxypeganine,7-fluoro-6-hydroxy-5-methoxydeoxypeganine and7-iodo-6-hydroxy-5-methoxydeoxypeganine.
 3. The active substancecombination according to claim 1I wherein the pharmaceuticallyacceptable derivative of mecamylamine is selected from the groupconsisting of the salts of mecamylamine with halogen acids and simpleorganic acids.
 4. The active substance combination according to claim 1,wherein mecamylamine is present in a form selected from the groupconsisting of the racemic mixture of the two stereoisomers ofmecamylamine and one of the two stereoisomers of mecamylamine.
 5. Theactive substance combination according to claim 1, wherein themedicament is in the form of a combined administration form fordeoxypeganine or one of its pharmaceutically acceptable derivatives andmecamylamine or one of its pharmaceutically acceptable derivatives. 6.The active substance combination according to claim 1, wherein themedicament is in the form of separate administration forms fordeoxypeganine or one of its pharmaceutically acceptable derivatives andmecamylamine or one of its pharmaceutically acceptable derivatives. 7.The active substance combination according to claim 1, wherein themedicament is in the form of an administration form to be administeredorally or parenterally.
 8. The active substance combination according toclaim 7, wherein said medicament in the form of a medicament having adepot effect.
 9. The active substance combination according to claim 1,wherein an administration form for a daily dose comprises 50 to 750 mgof deoxypeganine or one of its pharmaceutically acceptable salts in thecase of an administration form to be administered orally.
 10. The activesubstance combination according to claim 1, wherein an administrationform for a daily dose comprises 50 to 250 mg of deoxypeganine or one ofits pharmaceutically acceptable salts in the case of an administrationform to be administered transdermally.
 11. The active substancecombination according to claim 1, wherein an administration form for adaily dose comprises 2.5 to 20 mg of mecamylamine in the case of anadministration form to be administered orally.
 12. The active substancecombinations according to claim 1, wherein an administration form for adaily dose comprises 0.5 to 10 mg of mecamylamine in the case of anadministration form with delayed release.
 13. The treatment of alcoholabuse and/or alcohol dependencies comprising administrating comprisingdeoxypeganine or one of its pharmaceutically acceptable derivatives andmecamylamine or one of its pharmaceutically acceptable derivatives. 14.A process for treating alcohol abuse and/or alcohol dependence,comprising the steps of administrating an active substance combinationcomprising deoxypeganine or one of its pharmaceutically acceptablederivatives and mecamylamine or one of its pharmaceutically acceptablederivatives.
 15. The process according to claim 14, further comprisingthe step of pre-treatment with mecamylamine before administrating theactive substance combination.
 16. The active substance combinationaccording to claim 3, wherein said simple organic acids are selectedfrom the group consisting of tartaric acid, succinic acid and maleicacid.
 17. The active substance combination according to claim 7, whereinthe medicament is in the form of an administration form to beadministered transdermally.
 18. The active substance combinationaccording to claim 9, wherein the daily dose of deoxypeganine or one ofits pharmaceutically acceptable salts in the case of an administrationform to be administered orally is 100 to 400 mg.
 19. The activesubstance combination according to claim 11, wherein the daily dose ofmecamylamine in the case of an administration form to be administeredorally is 2.5 to 7.5 mg.
 20. The process according to claim 15, whereinthe pre-treatment step comprises daily doses of between 0.5 and 29 mg ofracemic mecamylamine or the individual isomers of mecamylamine andwherein the pre-treatment step lasts between 1 and 5 days.